Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Homo sapiens

Increased MITF expression contributes to melanoma progression and resistance to BRAF pathway inhibition. We show that, unexpectedly, lack of MITF is associated with more severe resistance to a range of inhibitors. Indeed, the presence of endogenous MITF was essential for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlated with expression of several activated receptor tyrosine kinases, most commonly AXL. The MITF-low/AXL-high/drug resistance phenotype was seen in roughly half of BRAF mutant and the majority of NRAS mutant melanoma cell lines. The dichotomous behavior of MITF in drug response was corroborated in vemurafenib-resistant biopsies, including MITF high and low clones in a relapsed patient. Drug cocktails containing AXL inhibitor enhanced melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. Overall design: Experssion analysis by RNAseq of 14 melanoma cell lines.

小眼畸形相关转录因子（MITF）表达上调可促进黑色素瘤进展及对BRAF通路抑制剂的耐药性。我们的研究意外发现，MITF缺失与对多种抑制剂的更严重耐药性相关。事实上，内源性MITF的存在是获得显著药物应答反应的必要条件。无论是原发性耐药还是获得性耐药场景中，MITF表达水平均与多种活化受体酪氨酸激酶的表达呈负相关，其中最常见的为AXL受体酪氨酸激酶（AXL）。MITF低表达/AXL高表达/药物耐药表型约出现在半数BRAF突变型及多数NRAS突变型黑色素瘤细胞系中。在维莫非尼（vemurafenib）耐药的活检样本中，MITF在药物应答中的双向调控特性得到了验证：1例复发患者的活检组织中同时存在MITF高表达与低表达克隆。包含AXL抑制剂的联合用药方案可增强BRAF或ERK抑制剂对黑色素瘤细胞的杀伤效果。本研究结果表明，MITF/AXL低比值可预测肿瘤对多种靶向药物的早期耐药性，同时支持AXL抑制剂用于克服BRAF突变型与NRAS突变型MITF低表达黑色素瘤的耐药性，这一策略有待临床验证。
实验设计：对14株黑色素瘤细胞系进行RNA测序（RNA-seq）表达分析。